Inhibition of Notch signaling prevents experimental fibrosis and induces regression of established fibrosis

Clara Dees, Pawel Zerr, Michal Tomcik, Christian Beyer, Angelika Horn, Alfiya Akhmetshina, Katrin Palumbo, Nicole Reich, Jochen Zwerina, Michael Sticherling, Mark P. Mattson, Oliver Distler, Georg Schett, Jörg H W Distler

Research output: Contribution to journalArticlepeer-review

Abstract

Objective: Tissue fibrosis caused by pathologic activation of fibroblasts with increased synthesis of extracellular matrix components is a major hallmark of systemic sclerosis (SSc). Notch signaling regulates tissue differentiation, and abnormal activation of Notch signaling has been implicated in the pathogenesis of various malignancies. The present study was undertaken to investigate the role of Notch signaling in SSc and to evaluate the therapeutic potential of Notch inhibition for the treatment of fibrosis. Methods: Activation of the Notch pathways was analyzed by staining for the Notch intracellular domain (NICD) and quantification of levels of HES-1 messenger RNA. In the mouse model of bleomycin-induced dermal fibrosis and in tight skin 1 mice, Notch signaling was inhibited by the γ-secretase inhibitor DAPT and by overexpression of a Notch-1 antisense construct. Results: Notch signaling was activated in SSc in vivo, with accumulation of the NICD and increased transcription of the target gene HES-1. Overexpression of a Notch antisense construct prevented bleomycin-induced fibrosis and hypodermal thickening in tight skin 1 mice. Potent antifibrotic effects were also obtained with DAPT treatment. In addition to prevention of fibrosis, targeting of Notch signaling resulted in almost complete regression of established experimental fibrosis. Conclusion: The present results demonstrate that pharmacologic as well as genetic inhibition of Notch signaling exerts potent antifibrotic effects in different murine models of SSc. These findings might have direct translational implications because different inhibitors of the γ-secretase complex are available and have yielded promising results in cancer trials.

Original languageEnglish (US)
Pages (from-to)1396-1404
Number of pages9
JournalArthritis and Rheumatism
Volume63
Issue number5
DOIs
StatePublished - May 2011
Externally publishedYes

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Rheumatology
  • Pharmacology (medical)

Fingerprint Dive into the research topics of 'Inhibition of Notch signaling prevents experimental fibrosis and induces regression of established fibrosis'. Together they form a unique fingerprint.

Cite this